DESCRIPTION: Identification of the mechanism(s) through which HIV leads to depletion of both CD4 and CD8 T cells has been elusive. A multitude of mechanisms have been postulated, generally falling into two broad categories; direct killing of the HIV infected cell or indirect death of HIV of uninfected T cells by HIV dependent mechanisms. The envelope of HIV(env) can mediate death of both infected and uninfected T cells. The discovery of chemokine receptors as HIV co-receptors has provided the opportunity to study their potential role in mediating env-triggered T cell death. A number of preliminary data have been obtained indicating that R5 and X4HIV, and their corresponding receptors exert T cell death through distinct molecular mechanisms. R5env leads to a Fas- and caspase-dependent death of uninfected CD4 T cells. On the contrary, X4env leads to a Fas- and caspase-independent death of not only uninfected CD4 but also CD8 T cells, as well as HIV infected CD4 T cells. This has prompted us to hypothesize that env can mediate death of both uninfected and HIV infected T cells (including CD8 T cells) and that the molecular mechanism mediating such death is ultimately dependent on the type of chemokine receptor engaged by env. To address this hypothesis we propose the following three specific aims I) Study the signal transduction pathways whereby X4env leads to the death of uninfected CD4 and CD8 T cells via CXCR4. II) Determine how the R5env interaction with CD4 and CCR- leads to Fas dependent apoptosis. III) Document the necessary role of env in mediating killing of HIV infected T cells through its interaction with the corresponding chemokine receptor and translate such findings to lymphoid tissue from HIV infected patients. Identification of the molecular mechanisms and second messengers whereby CCR- and CXCR4 mediate T cell death will help in determining how HIV infection ultimately ravages the immune system. The implications derived from chemokine receptor mediated death can also be expanded to other non CD4 T cells known to be targeted during the course of HIV infection and to express chemokine receptors such as neurons, epithelial cells, and NK cells.